Geoffrey Beene Cancer Research Center: 2011 Geoffrey Beene Grant Awards

The following investigators were awarded Geoffrey Beene Cancer Research grants in 2011:

Pictured: Michael BergerMichael Berger, PhD
Department of Pathology
Project: High-Throughput Profiling of Genomic Alterations in Clinical Tumor Specimens

Project Abstract
Efforts to understand cancer at the molecular level have revealed genetic biomarkers that reflect the nature and course of disease and, in some cases, predict the likelihood that a patient will benefit from a particular treatment. We plan to develop and apply a robust and cost-effective methodology, empowered by massively parallel “next-generation” sequencing, by which any clinical tumor specimen may be characterized for DNA mutations and copy number changes in all known cancer genes. By systematically deploying this platform across clinically annotated tumors and, ultimately, every cancer patient at Memorial Sloan Kettering, we hope to facilitate individual approaches to cancer treatment through improved diagnostics and the identification of novel biomarkers.

Pictured: Sarat ChandarlapatySarat Chandarlapaty, MD, PhD
Breast Cancer Service, Department of Medicine
Human Oncology and Pathogenesis Program
Molecular Pharmacology and Chemistry Program
Project: Targeting AKT Inhibitor-Induced Feedback Signaling in Breast Cancer

Project Abstract
The PI3K/AKT/mTOR pathway is mutationally activated in the majority of breast cancers. While this pathway is druggable by a variety of compounds, the pathway is subject to multiple forms of negative feedback regulation and these feedback pathways become relieved under conditions of drug inhibition of the pathway. We hypothesize that loss of negative feedback limits the effectiveness of drugs targeting this pathway. We propose to (1) identify the specific mechanisms of feedback regulation of PI3K/AKT/mTOR-pathway-activated breast cancers, (2) determine the consequence of loss of negative feedback on the efficacy of drug therapy, and (3) clinically evaluate combining an AKT inhibitor with an inhibitor of a known oncogenic pathway that is hyperactivated through AKT-inhibitor-mediated loss of feedback.

Pictured: Eric HollandEric Holland, MD, PhD
Cancer Biology and Genetics Program
Department of Neurosurgery
Project: Understanding Clonal Evolution and Heterogeneity of the Therapeutic Response by Lineage Tracing in Mouse Models of Glioma

Project Abstract
It is increasingly appreciated that cancer cells within any given tumor differ considerably from each other, and such heterogeneity is likely a major hurdle in cancer therapeutics. Still, little is known about the mechanisms underlying the emergence of tumor cell heterogeneity. Traditionally, all cells within the tumor have been assumed to originate from a common ancestor. However, in addition to bona fide tumor cells, solid tumors also contain numerous cells derived from the normal host microenvironment such as blood vessels and immune cells. In brain tumors, a large number of normal brain cells are trapped within the growing tumor. Our research indicates that such normal cells can become corrupted by the tumor environment and actually become bona fide tumor cells themselves, suggesting that cancer cells within the same tumor may be unrelated to each other and may thus differ considerably in their response to specific therapeutic agents. By developing a new mouse model, we aim to characterize the corruption of such initially normal brain cells within gliomas, a common group of brain tumors, specifically with regard to their contribution to resistance to commonly used anticancer therapeutics and tumor recurrence.

Pictured: Xuejun JiangXuejun Jiang, PhD
Cell Biology Program
Project: Mechanism and Therapeutic Potential of PTEN Regulation upon Hypoxia

Project Abstract
The overall goal of this proposal is to understand the molecular basis underlying the context-specific regulation of PTEN tumor suppressor, and the cancer therapeutic implication of such regulation. Specifically, we will study how the ubiquitin ligase NEDD4-1 regulates PTEN function, AKT activation, cell survival/apoptosis, and tumorigenesis in the context of hypoxia. Success of this study will not only elucidate the molecular mechanisms governing the context-specific regulation of PTEN and novel aspects of hypoxia biology, but will also provide insights into therapeutic targeting of the NEDD4-1-PTEN circuitry in treating specific human cancers.

Pictured: Moritz KircherMoritz Kircher, MD, PhD
Department of Radiology
Project: Combined Pre- and Intraoperative Brain Tumor Imaging Using a Novel Dual-Modality Raman-MRI Nanoparticle Probe

Project Abstract
Malignant brain tumors remain a therapeutic challenge, in part because of the difficulty of visualizing the tumor borders during surgical resection. Our project seeks to validate a new molecular approach to brain tumor imaging based on a dual-modality MRI/SERS (surface-enhanced Raman spectroscopy) nanoparticle, allowing combined preoperative staging and intraoperative high-resolution imaging using a single contrast agent. This will include biodistribution and cytotoxicity studies and assessment of the accuracy of tumor delineation by MRI and Raman imaging in transgenic mouse models.   

Pictured: Robert KleinRobert Klein, PhD
Cancer Biology and Genetics Program
Project: Transcriptional Regulatory SNPs as a Mechanism for Prostate Cancer Risk Loci

Project Abstract
While genome-wide-association studies have identified numerous single nucleotide polymorphisms (SNPs) associated with risk of prostate cancer and other diseases, little is known about the biological mechanism by which these SNPs operate.  Here, we will test the hypothesis that the functional allele(s) at many prostate cancer risk loci alter a functional transcription factor binding site, thereby resulting in misregulation of nearby gene(s) that influence the carcinogenesis process. This research will give new insight into the biology of prostate cancer by identifying both a general mechanism underlying prostate cancer risk SNPs and specific genes that may mediate this altered risk.

Pictured: Jason LewisJason Lewis, PhD
Vice Chair for Research, Department of Radiology
Chief, Radiochemistry Service
Molecular Pharmacology and Chemistry Program
Project: Development of 89Zr-5A10 for the Measurement of AR Signaling in Advanced Prostate Cancer with Positron Emission Tomography

Project Abstract
We propose to evaluate 89Zr-5A10 as a pharmacodynamic and predictive biomarker for two important classes of therapies for CRPC (antiandrogens and PI3K inhibitors) and to conduct a phase 0 study with a humanized version of 5A10 in rodents and men with CRPC. This translational project represents one of the first systematic efforts to develop a biomarker for the evaluation of AR signaling in patients with CRPC, and the findings from this proposal have the potential to substantially impact the customization of individual patient care, as well as influence the design and execution of future clinical trials.

Pictured: Paul PaikPaul Paik, MD
Thoracic Oncology Service, Department of Medicine
Project: Squamous Cell Carcinoma of the Lung Mutation Analysis Program (SQC-MAP)

Project Abstract
Patients with squamous cell carcinomas of the lung (SQCLC) comprise 20 percent of all non-small cell lung cancers diagnosed in the United States annually, amounting to nearly 40,000 patients per year. Unfortunately, no targeted therapies have been identified for these patients, this despite the success of drugs that target the mutant epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) in a third of lung adenocarcinoma (ADCL) cases. Exciting new work has identified putative driver oncogenic events in upwards of 50 to 60 percent of SQCLC patients. The complex nature of these mutations, which have almost no overlap with those found in ADCL, necessitates the creation of a new molecular profiling infrastructure. SQ-MAP will fulfill this role, prospectively validating these molecular aberrations in a cohort of 100 SQCLC patients at Memorial Sloan Kettering while simultaneously serving as the platform by which patients will be paired to emerging clinical trials of new targeted therapies.   

Pictured: Simon PowellSimon Powell, MD, PhD
Chair, Department of Radiation Oncology
Molecular Biology Program
Project: Genomic Determinants of Radiosensitivity

Project Abstract
The project aims to understand the genetic factors that underlie the individual differences in sensitivity to ionizing radiation. We have developed a high-throughput assay of DNA damage and repair using flow cytometry for lymphoblastoid cell lines. By studying the 1000 Genomes Project cell lines, where whole genome sequencing data are available, we can study genetic locus association markers for radiation sensitivity as well as candidate mutations and polymorphisms in known radiation response genes. The ultimate goal is to develop a radiogenomics profile for predicting sensitivity or resistance to radiation that will help in planning radiation therapy.

Pictured: Marcel R.M. van den BrinkMarcel van den Brink, MD, PhD
Head, Division of Hematologic Oncology
Immunology Program
Project: Endothelial Precursor Cells in Allogeneic Bone Marrow Transplantation during Graft-versus-Host Disease and Graft-versus-Tumor Activity

Project Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important therapy with curative potential for a variety of malignant and non-malignant diseases. The major obstacles to a more favorable therapeutic outcome are tumor relapse and acute graft-versus-host disease (GVHD), which is an inflammatory process primarily involving the intestine, liver, and skin. Neovascularization has been implicated in both tumor growth and inflammation suggesting that neovascularization could be an attractive therapeutic target in patients with malignancies undergoing HSCT. Based upon our promising preclinical studies we hypothesize that therapeutic targeting of neovascularization in allo-HSCT recipients can simultaneously ameliorate GVHD and inhibit post-transplant malignant relapse resulting in improved overall survival in allo-HSCT recipients.

Pictured: Andrea VenturaAndrea Ventura, MD, PhD
Cancer Biology and Genetics Program
Project:  Investigating the miR-34 Family of Tumor Suppressor MicroRNAs

Project Abstract
Over the past decade, microRNAs (miRNAs) have emerged as key modulators of gene expression in metazoan and plants. Deregulated expression of miRNAs is a common feature of human cancers, and a number of miRNAs have been proposed to act as oncogenes or tumor suppressors. We will investigate a recently described family of p53-regulated miRNAs whose members have been proposed to act as tumor suppressors in a variety of human cancers. By combining in vivo studies in the mouse and high-throughput approaches we will determine the physiologic functions of the various members of this family of miRNAs, their potential activity as tumor suppressors, and their mechanism of action